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Fabrication and Characterization of Electrospun 75:25 PLGA Nanofibers for Skin Tissue Engineering
Abstract
Poly (lactic-co-glycolic) acid (PLGA) is a biodegradable polymer that has been extensively used in various tissue engineering applications. In this study, the potential of using scaffolds made of fibrous PLGA films for skin reconstruction and drug delivery was investigated. The mechanical properties of the films, the short term release kinetics, the glass transition temperature as well the morphology are assessed. Samples of PLGA 75:25 (lactic acid/glycolic acid content ratio = 75:25) are tested. The modulus of elasticity (8.3-22.5 MPa), the ultimate tensile stress (0.150- 0.380 MPa), and the corresponding elongation were within the lower limits known for human skin and some soft tissues. The glass transition temperature of PLGA changed slightly (1.7%) post manufacturing and was higher than the average skin temperature. Moreover, short term release kinetics were slow which indicated that drug release could be controlled to locally deliver drugs over a prolonged period. Thus, in conclusion, biodegradable PLGA is promising for skin tissue engineering scaffold applications requiring further optimization and experimentation.
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The aim of this study is to investigate the applicability of poly(lactic-co-glycolic acid) (PLGA)/collagen composite scaffold for skin tissue engineering. PLGA and collagen were dissolved in HFIP as a common solvent and fibrous scaffolds were prepared by electrospinning method. The scaffolds were characterized by scanning electron microscopy (SEM), FTIR spectroscopy, mercury porosimetry, tensile strength, biocompatibility assays and Biodegradation. Cytotoxicity and cell adhesion were tested for two cell line groups, human dermal fibroblast (HDF) and human keratinocyte (HaCat). SEM images showed appropriate cell adhesion to the scaffold for both cell lines. MTT assays indicated that the cell viability of HDF cells increased with time, but the number of HaCat cells decreased after 14 days. The ultimate tensile strength was suitable for skin substitute application, but its elongation at break was rather low. For successful clinical application of the PLGA/collagen scaffold, some properties especially mechanical strain needs to be improved.
Significance: With an aging population leading to an increase in diabetes and associated cutaneous wounds, there is a pressing clinical need to improve wound-healing therapies. Recent Advances: Tissue engineering approaches for wound healing and skin regeneration have been developed over the past few decades. A review of current literature has identified common themes and strategies that are proving successful within the field: The delivery of cells, mainly mesenchymal stem cells, within scaffolds of the native matrix is one such strategy. We overview these approaches and give insights into mechanisms that aid wound healing in different clinical scenarios. Critical Issues: We discuss the importance of the biomimetic niche, and how recapitulating elements of the native microenvironment of cells can help direct cell behavior and fate. Future Directions: It is crucial that during the continued development of tissue engineering in wound repair, there is close collaboration between tissue engineers and clinici...
Electrospun poly(vinyl chloride) (PVC) nanofibrous were prepared by electrospinning. Various concentration of polyurethane (PU) were added to PVC solution for plasticization of the electrospun nanofibrous. The pristine and plasticized nanofibrous were characterized by field emission scanning electron microscopy (FE-SEM), differencial thermal analysis (DTA), and thermogravimetry analysis (TGA), respectively. Thermal properties form DTA and TGA results indicated that the addition of PU decreased glass transition temperature (Tg) of PVC and increased heat resistance of PVC nanofiber. The dielectric constant of plasticized nanofibrous measured using precision LCR meter indicated that the membrane were dense.
![Dieudonné [Radé] Baganizi](https://i1.rgstatic.net/ii/profile.image/279884166385671-1443740993173_Q64/Dieudonne-rade-Baganizi.jpg)
Over centuries, the field of regenerative skin tissue engineering has had several advancements to facilitate faster wound healing and thereby restoration of skin. Skin tissue regeneration is mainly based on the use of suitable scaffold matrices. There are several scaffold types, such as porous, fibrous, microsphere, hydrogel, composite and acellular, etc., with discrete advantages and disadvantages. These scaffolds are either made up of highly biocompatible natural biomaterials, such as collagen, chitosan, etc., or synthetic materials, such as polycaprolactone (PCL), and poly-ethylene-glycol (PEG), etc. Composite scaffolds, which are a combination of natural or synthetic biomaterials, are highly biocompatible with improved tensile strength for effective skin tissue regeneration. Appropriate knowledge of the properties, advantages and disadvantages of various biomaterials and scaffolds will accelerate the production of suitable scaffolds for skin tissue regeneration applications. At the same time, emphasis on some of the leading challenges in the field of skin tissue engineering, such as cell interaction with scaffolds, faster cellular proliferation/differentiation, and vascularization of engineered tissues, is inevitable. In this review, we discuss various types of scaffolding approaches and biomaterials used in the field of skin tissue engineering and more importantly their future prospects in skin tissue regeneration efforts.
Statement of significance:
Significant soft tissue loss resulting from traumatic injury or tumor resection often requires surgical reconstruction using autologous soft tissue flaps. However, the limited availability of qualitative autologous flaps as well as the donor site morbidity significantly limits this approach. Engineered soft tissue flap grafts may offer a clinically relevant alternative to the autologous flap tissue. In this study, we engineered vascularized soft tissue free flap by using skin/adipose flap extracellular matrix scaffold (DSAF) in combination with multiple types of human cells. Following vascular reanastomosis in the recipient site, the engineered products successful regenerated large-scale fat tissue in vivo. This approach may provide a translatable platform for composite soft tissue free flap engineering for microsurgical reconstruction.
Electrospinning is a process that produces continuous polymer fibers with diameters of a nanometric scale. Nylon 6 in formic acid was electrospun to obtain the nanofibers. Fibers with different diameters were obtained using flow rates of 0.1, 0.5, 1 and 1.5 mL/hr, 20 wt% solution concentration, with an applied voltage of 20 kV and 15 cm spinning distance. Flow rate influenced the fiber diameter distribution, droplet size and its initiating shape at the capillary tip, the trajectory of the jet, maintenance of Taylor cone, areal density and nanofiber morphology. The morphology of the electrospun nanofibers was analyzed by using the scanning electron microscope (SEM). The effect of flow rate on the deposition area was also investigated for better control of the process. It was observed that a stabilized Taylor cone, small average droplet size, narrowest fiber diameter distribution, more stability in the originating jet, and uniform morphology of nanofiber is obtained at a flow rate of 0.5 mL/hr.
The effect of flow rate on the diameter of the charged jet in the
electrospinning process is studied theoretically. The obtained theoretical
results offer in-depth physical understanding and mechanism of nanoporous
fibers. It also reveals that the morphology and diameter of nanoporous
microspheres can be controlled by the flow rate.
Co-polymers of lactide and glycolide, referred to as PLGA, have generated tremendous interest because of their excellent biocompatibility, biodegradability and mechanical strength. Various polymeric devices like microspheres, microcapsules, nanoparticles, pellets, implants, and films have been fabricated using these polymers. They can be transformed by spinning into filaments for subsequent fabrication of desirable textile structures. Spinning may be accomplished by various routes. The fibers may be fabricated into various forms and may be used for implants and other surgical applications such as sutures. They are also easy to formulate into various delivery systems for carrying a variety of drug classes. The present article presents a review on the production of PLGA fiber by various methods, along with correlations between structure and properties of the fibers. The applications of these fibers in biomedical domains are also discussed.
Poly(lactic-co-glycolic) acid (PLGA) has attracted considerable interest as a base material for biomedical applications due to its: (i) biocompatibility; (ii) tailored biodegradation rate (depending on the molecular weight and copolymer ratio); (iii) approval for clinical use in humans by the U.S. Food and Drug Administration (FDA); (iv) potential to modify surface properties to provide better interaction with biological materials; and (v) suitability for export to countries and cultures where implantation of animal-derived products is unpopular. This paper critically reviews the scientific challenge of manufacturing PLGA-based materials with suitable properties and shapes for specific biomedical applications, with special emphasis on bone tissue engineering. The analysis of the state of the art in the field reveals the presence of current innovative techniques for scaffolds and material manufacturing that are currently opening the way to prepare biomimetic PLGA substrates able to modulate cell interaction for improved substitution, restoration, or enhancement of bone tissue function.
Poly(glycolic acid) (PGA) has long been a popular polymer in the tissue engi-neering field. PGA possesses many favorable properties such as biocompati-bility, bioabsorbability, and tensile strength. The traditional fiber formation techniques of melt extrusion and cold-drawing are generally limited to fibers of 10-12 µm in diameter. Electrostatic spinning, or electrospinning, is an attractive approach for the production of much smaller diameter fibers which are of interest as tissue engineering scaffolds. We demonstrate the ability to control the fiber diameter of PGA as a function of solution concentration and fiber orientation, as well as show a correlation between the fiber orientation, elastic modulu, and strain to failure of PGA in a uniaxial model.
Future biomaterials must simultaneously enhance tissue regeneration while minimizing immune responses and inhibiting infection.
While the field of tissue engineering has promised to develop materials that can promote tissue regeneration for the entire
body, such promises have not become reality. However, tissue engineering has experienced great progress due to the recent
emergence of nanotechnology. Specifically, it has now been well established that increased tissue regeneration can be achieved
on almost any surface by employing novel nano-textured surface features. Numerous studies have reported that nanotechnology
accelerates various regenerative therapies, such as those for the bone, vascular, heart, cartilage, bladder and brain tissue.
Various nano-structured polymers and metals (alloys) have been investigated for their bio (and cyto) compatibility properties.
This review paper discusses several of the latest nanotechnology findings in regenerative medicine (also now called nanomedicine)
as well as their relative levels of success.
KeywordsNanotechnology-Tissue engineering-Orthopedic-Vascular-Neural-Skin-Cellular and protein interactions
In past two decades poly lactic-co-glycolic acid (PLGA) has been among the most attractive polymeric candidates used to fabricate devices for drug delivery and tissue engineering applications. PLGA is biocompatible and biodegradable, exhibits a wide range of erosion times, has tunable mechanical properties and most importantly, is a FDA approved polymer. In particular, PLGA has been extensively studied for the development of devices for controlled delivery of small molecule drugs, proteins and other macromolecules in commercial use and in research. This manuscript describes the various fabrication techniques for these devices and the factors affecting their degradation and drug release.
Degrapol® and PLGA electrospun fiber fleeces were characterized with regard to fiber diameter, alignment, mechanical properties as well as scaffold porosity. The study showed that electrospinning parameters affect fiber diameter and alignment in an inverse relation: fiber diameter was increased with increased flow rate, with decrease in working distance and collector velocity, whereas fiber alignment increased with the working distance and collector velocity but decreased with increased flow rate. When Degrapol® or PLGA-polymers were co-spun with increasing ratios of a water-soluble polymer that was subsequently removed; fibrous scaffolds with increased porosities were obtained. Mechanical properties correlated with fiber alignment rather than fiber diameter as aligned fiber scaffolds demonstrated strong mechanical anisotropy. For co-spun fibers the Young's modulus correlated inversely with the amount of co-spun polymer. Cell proliferation was independent of the porosity of the scaffold, but different between the two polymers. Furthermore, fibrous scaffolds with different porosities were analyzed for cell infiltration suggesting that cell infiltration was enhanced with increased porosity and increasing time. These experiments indicate that 3D-fiber fleeces can be produced with controlled properties, being prerequisites for successful scaffolds in tissue engineering applications.
The skin acts as a barrier to exogenous substances, pathogens, and trauma. Skin defects caused by burns, venous ulcer, diabetic ulcer, or acute injury occasionally induce life-threatening situations. Tissue engineering provides an alternative for autologous or allogeneic tissue transplantation, which is required because of donor site limitations and the risks of transmitting infection. Currently, skin substitutes are made of only extracellular matrix, mainly cells, or combination of cells and matrices. New biotechnological approaches have led to the development of the skin equivalent, the closest match yet to native human skin in terms of histological and functional properties. This review article focuses upon the development of the in vitro and in vivo epidermis and dermis and their clinical applications.
Background:
Skin substitutes are frequently used by plastic surgeons today to treat a wide variety of cutaneous defects. They provide methods to heal wounds while minimizing donor sites. They are commonly used in burns, acute wounds, and chronic wounds.
Methods:
The authors reviewed the literature on both the development of skin substitutes and their use today. The authors focused their work on what are currently the more commonly used types of skin substitutes in the United States. There is a wide interest in human-derived placental products, which will be the subject of a future publication.
Results:
Commonly used skin substitutes include semisynthetic dermal scaffolds, allogenic cell constructs, and cellular and decellularized allogenic or xenogenic sources. For semisynthetic dermal scaffolds and allogenic cell constructs, there have been large clinical trials demonstrating their efficacy.
Conclusions:
Skin substitutes represent great progress for plastic surgery and provide several advances and options with which to heal wounds. More studies are needed to guide surgeons into the most appropriate use of these materials. Future developments, including advances in scaffolds, stem cells, and tissue processing, are likely to produce even more clinical options for our patients.
The paucity of cellular and molecular signals essential for normal wound healing makes severe dermatological ulcers stubborn to heal. The novel strategies of skin regenerative treatments are focused on the development of biologically responsive scaffolds accompanied by cells and multiple biomolecules resembling structural and biochemical cues of the natural extracellular matrix (ECM). Electrospun nanofibrous scaffolds provide similar architecture to the ECM leading to enhancement of cell adhesion, proliferation, migration and neo tissue formation. This Review surveys the application of biocompatible natural, synthetic and composite polymers to fabricate electrospun scaffolds as skin substitutes and wound dressings. Furthermore, the application of biomolecules and therapeutic agents in the nanofibrous scaffolds viz growth factors, genes, antibiotics, silver nanoparticles, and natural medicines with the aim of ameliorating cellular behavior, wound healing, and skin regeneration are discussed.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Dermal tissue engineering focuses on the restoration of diseased and damaged tissues by using a combination of cells, biomaterials, and bioactive molecules. Inorganic substances like zeolites, clay, mesoporous silica, metals, and metal oxides are advanced materials used in wound healing research. They can improve the structural stability and bioactivity of bio polymeric scaffolds. Zeolites, clays, and mesoporous silica act as suitable carriers for drug delivery and when incorporated within scaffolds, serve as ideal matrices for promoting skin regeneration. This review focuses on various natural polymers/inorganic materials based composite scaffolds used for skin tissue engineering, highlighting their synthesis routes and mode of action by which wound healing is enhanced. Among the different inorganic materials used, the role of zeolites incorporated biocomposites for promoting blood coagulation, antibacterial effect; oxygen delivery to cells and wound healing are discussed in detail. The article thus includes recent attempts to explore the hidden potential of inorganic materials in dermal tissue engineering.
Electrospinning is a technique used to produce micron to submicron diameter polymeric fibers. The surface of electrospun fibers is important when considering end-use applications. For example, the ability to introduce porous surface features of a known size is required if nanoparticles need to be deposited on the surface of the fiber or if drug molecules are to be incorporated for controlled release. Surface features, or pores, became evident when electrospinning in an atmosphere with more than 30% relative humidity. Increasing humidity causes an increase in the number, diameter, shape, and distribution of the pores. Increasing the molecular weight of the polystyrene (PS) results in larger, less uniform shaped pores. This work includes an investigation of how humidity and molecular weight affect the surface of electrospun PS fibers. The results of varying the humidity and molecular weight on the surface of electrospun PS fibers were studied using optical microscopy, field emission scanning electron microscopy (FESEM), and atomic force microscopy (AFM) coupled with image analysis.
The electrospinning of polyglycolide (PGA), poly(L-lactide) (PLA), and poly(lactide-co-glycolide) (PLGA; L-lactide/glycolide = 50/50) was performed with chloroform or 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) as a spinning solvent to fabricate their nanofiber matrices. The morphology of the electrospun PGA, PLA, and PLGA nanofibers was investigated with scanning electron microscopy (SEM). The PLGA nanofibers, electrospun with a nonpolar chloroform solvent, had a relatively large average diameter (760 nm), and it had a relatively broad distribution in the range of 200–1800 nm. On the other hand, the PGA and PLA fibers, electrospun with a polar HFIP solvent, had a small average diameter (∼300 nm) with a narrow distribution. This difference in the fiber diameters may be associated with the polarity of the solvent. Also, the in vitro degradation of PGA, PLA, and PLGA nanofiber matrices was examined in phosphate buffer solutions (pH 7.4) at 37°C. The degradation rates of the nanofiber matrices were fast, in the order of PGA > PLGA ≫ PLA. Structural and morphological changes during in vitro degradation were investigated with differential scanning calorimetry and wide-angle X-ray diffraction. For the PGA matrix, a significant increase in the crystallinity during the early stage was detected, as well as a gradual decrease during the later period, and this indicated that preferential hydrolytic degradation in the amorphous regions occurred with cleavage-induced crystallization, followed by further degradation in the crystalline region. © 2004 Wiley Periodicals, Inc. J Appl Polym Sci 95: 193–200, 2005
Biodegradable scaffolds have played an important role in a number of tissue engineering attempts over the past decade. The goal of this review article is to provide a brief overview of some of the important issues related to scaffolds fabricated from synthetic biodegradable polymers. Various types of such materials are available; some are commercialized and others are still in the laboratories. The properties of the most common of these polymers are discussed here. A variety of fabrication techniques were developed to fashion polymeric materials into porous scaffolds, and a selection of these is presented. The very important issue of scaffold architecture, including the topic of porosity and permeability, is discussed. Other areas such as cell growth on scaffolds, surface modification, scaffold mechanics, and the release of growths factors are also reviewed. A summary outlining the common themes in scaffold-related science that are found in the literature is presented. © 2001 John Wiley & Sons, Inc. J Biomed Mater Res, 55, 141–150, 2001
The in vitro degradation behaviour of non-porous ultra-fine poly(glycolic acid)/poly(l-lactic acid) (PGA/PLA) fibres and porous ultra-fine PGA fibres was investigated. The non-porous ultra-fine PGA/PLA fibres were prepared by electrospinning of a PGA/PLA solution in 1,1,1,3,3,3-hexafluoro-2-propanol and the porous ultra-fine PGA fibres were obtained from them via selective removal of PLA with chloroform. Since PLA has a lower degradation rate than PGA, the degradation rates of the ultra-fine PGA/PLA fibres decreased with increasing content of PLA. The porous ultra-fine PGA fibres were degraded in vitro in the order of non-porous PGA > P-PGA/PLA(90/10) > P-PGA/PLA(70/30) > P-PGA/PLA(50/50) > P-PGA/PLA(30/70) due to autocatalytic hydrolysis.
Electrospinning has been recognized as an efficient technique for the fabrication of polymer nanofibers. Various polymers have been successfully electrospun into ultrafine fibers in recent years mostly in solvent solution and some in melt form. Potential applications based on such fibers specifically their use as reinforcement in nanocomposite development have been realized. In this paper, a comprehensive review is presented on the researches and developments related to electrospun polymer nanofibers including processing, structure and property characterization, applications, and modeling and simulations. Information of those polymers together with their processing conditions for electrospinning of ultrafine fibers has been summarized in the paper. Other issues regarding the technology limitations, research challenges, and future trends are also discussed.
The aim of this study was to fabricate dual drug-loaded poly(lactic-co-glycolic acid) (PLGA)/mesoporous silica nanoparticles (MSNs) electrospun composite mat, with the two model drugs (fluorescein (FLU) and rhodamine B (RHB)) releasing in separate and distinct release kinetics. The PLGA-based electrospun mat loading with the same amount of FLU (5%, with respect to the weight of PLGA) and different amounts of RHB-loaded MSNs (5, 15 and 25%, with respect to the weight of PLGA) were prepared and studied for their releasing properties. The morphology of the composite mats was characterized by scanning electron microscopy and transmission electron microscopy. Finally, the release profiles of the dual drug-loaded electrospun mats were measured, and the results indicated that the FLU and RHB released from the PLGA/FLU/RHB-loaded MSNs electrospun mats showed separate and distinct profiles. Most of the FLU was released rapidly during the 324 h of the trial; however, RHB showed a sustained release behavior, and the release rate could be controlled by the content of the RHB-loaded MSNs in the electrospun mat.
The architecture of an engineered tissue substitute plays an important role in modulating tissue growth. A novel poly(D,L-lactide-co-glycolide) (PLGA) structure with a unique architecture produced by an electrospinning process has been developed for tissue-engineering applications. Electrospinning is a process whereby ultra-fine fibers are formed in a high-voltage electrostatic field. The electrospun structure, composed of PLGA fibers ranging from 500 to 800 nm in diameter, features a morphologic similarity to the extracellular matrix (ECM) of natural tissue, which is characterized by a wide range of pore diameter distribution, high porosity, and effective mechanical properties. Such a structure meets the essential design criteria of an ideal engineered scaffold. The favorable cell-matrix interaction within the cellular construct supports the active biocompatibility of the structure. The electrospun nanofibrous structure is capable of supporting cell attachment and proliferation. Cells seeded on this structure tend to maintain phenotypic shape and guided growth according to nanofiber orientation. This novel biodegradable scaffold has potential applications for tissue engineering based upon its unique architecture, which acts to support and guide cell growth.
The present work utilizes electrospinning to fabricate synthetic polymer/DNA composite scaffolds for therapeutic application in gene delivery for tissue engineering. The scaffolds are non-woven, nano-fibered, membranous structures composed predominantly of poly(lactide-co-glycolide) (PLGA) random copolymer and a poly(D,L-lactide)-poly(ethylene glycol) (PLA-PEG) block copolymer. Release of plasmid DNA from the scaffolds was sustained over a 20-day study period, with maximum release occurring at approximately 2 h. Cumulative release profiles indicated amounts released were approximately 68-80% of the initially loaded DNA. Variations in the PLGA to PLA-PEG block copolymer ratio vastly affected the overall structural morphology, as well as both the rate and efficiency of DNA release. Results indicated that DNA released directly from these electrospun scaffolds was indeed intact, capable of cellular transfection, and successfully encoded the protein beta-galactosidase. When tested under tensile loads, the electrospun polymer/DNA composite scaffolds exhibited tensile moduli of approximately 35 MPa, with approximately 45% strain initially. These values approximate those of skin and cartilage. Taken together, this work represents the first successful demonstration of plasmid DNA incorporation into a polymer scaffold using electrospinning.
We investigated the potential of a nanofiber-based poly(DL-lactide-co-glycolide) (PLGA) scaffold to be used for cartilage reconstruction. The mechanical properties of the nanofiber scaffold, degradation of the scaffold and cellular responses to the scaffold under mechanical stimulation were studied. Three different types of scaffold (lactic acid/glycolic acid content ratio = 75 : 25, 50 : 50, or a blend of 75 : 25 and 50 : 50) were tested. The tensile modulus, ultimate tensile stress and corresponding strain of the scaffolds were similar to those of skin and were slightly lower than those of human cartilage. This suggested that the nanofiber scaffold was sufficiently mechanically stable to withstand implantation and to support regenerated cartilage. The 50 : 50 PLGA scaffold was degraded faster than 75 : 25 PLGA, probably due to the higher hydrophilic glycolic acid content in the former. The nanofiber scaffold was degraded faster than a block-type scaffold that had a similar molecular weight. Therefore, degradation of the scaffold depended on the lactic acid/glycolic acid content ratio and might be controlled by mixing ratio of blend PLGA. Cellular responses were evaluated by examining toxicity, cell proliferation and extracellular matrix (ECM) formation using freshly isolated chondrocytes from porcine articular cartilage. The scaffolds were non-toxic, and cell proliferation and ECM formation in nanofiber scaffolds were superior to those in membrane-type scaffolds. Intermittent hydrostatic pressure applied to cell-seeded nanofiber scaffolds increased chondrocyte proliferation and ECM formation. In conclusion, our nanofiber-based PLGA scaffold has the potential to be used for cartilage reconstruction.
Microenvironments appear important in stem cell lineage specification but can be difficult to adequately characterize or control with soft tissues. Naive mesenchymal stem cells (MSCs) are shown here to specify lineage and commit to phenotypes with extreme sensitivity to tissue-level elasticity. Soft matrices that mimic brain are neurogenic, stiffer matrices that mimic muscle are myogenic, and comparatively rigid matrices that mimic collagenous bone prove osteogenic. During the initial week in culture, reprogramming of these lineages is possible with addition of soluble induction factors, but after several weeks in culture, the cells commit to the lineage specified by matrix elasticity, consistent with the elasticity-insensitive commitment of differentiated cell types. Inhibition of nonmuscle myosin II blocks all elasticity-directed lineage specification-without strongly perturbing many other aspects of cell function and shape. The results have significant implications for understanding physical effects of the in vivo microenvironment and also for therapeutic uses of stem cells.